Airway hyperresponsiveness (AHR) is a key physiological component of asthma. While AHR is inducible in experimental animal models by sensitization to antigen and can be potentiated by antigen challenge in sensitized humans, it is also evident in non-sensitized (naive) individuals. The genetic basis of this complex trait has remained elusive. Analysis of mice that demonstrate heritable naive airway hyperresponsiveness provides a means to identify its underlying molecular basis. We have previously used genetic mapping to identify quantitative trait loci (QTLs) that confer AHR. We have also used genetic and pharmacological analysis to demonstrate that this trait is mediated by mast cells. In this proposal, we plan to continue our investigation of the heritable loci that predispose to AHR using state-of-the-art genetic strategies, and to assess the role of mast cells in conferring the strain-specific AHR trait. PUBLIC HEALTH RELEVANCE: Increased airway responsiveness to stimuli is a physiological component of human asthma. Genetic analysis of mice that demonstrate airway hyperresponsiveness as heritable trait provides a means to identify its underlying molecular basis, and potentially a method to treat it.